Obesity accelerates cardiovascular ageing

Abstract

A global obesity pandemic, coupled with an increasingly ageing population, is exacerbating the burden of cardiovascular disease. Indeed, clinical and experimental evidence underscores a potential connection between obesity and ageing in the pathogenesis of various cardiovascular disorders. This is further supported by the notion that weight reduction not only effectively reduces major cardiovascular events in elderly individuals but is also considered the gold standard for lifespan extension, in obese and non-obese model organisms. This review evaluates the intricate interplay between obesity and ageing from molecular mechanisms to whole organ function within the cardiovascular system. By comparatively analysing their characteristic features, shared molecular and cell biological signatures between obesity and ageing are unveiled, with the intent to shed light on how obesity accelerates cardiovascular ageing. This review also elaborates on how emerging metabolic interventions targeting obesity might protect from cardiovascular diseases largely through antagonizing key molecular mechanisms of the ageing process itself. In sum, this review aims to provide valuable insight into how understanding these interconnected processes could guide the development of novel and effective cardiovascular therapeutics for a growing aged population with a concerning obesity problem.

Keywords: Autophagy; Caloric restriction; Cardiovascular disease; GLP-1; Inflammation; Mitochondrial dysfunction; SGLT2; Senescence.

Graphical Abstract

Figure 1

Trends of ageing, obesity, and cardiovascular disease between 1990 and 2021. This figure illustrates the rising trends in ageing, obesity, and cardiovascular disease over a 31-year period. It depicts the proportion of elderly and adults with obesity in Europe (WHO region) and globally, highlighting how these demographic shifts correlate with the increasing burden of cardiovascular diseases. Specifically, the figure shows the percentage of elderly individuals (≥65 years) as well as adults with obesity (BMI: >30 kg/m²) or cardiovascular diseases in Europe (A) and worldwide (B). Data on adults (>18 years) with obesity were extracted from the Global Health Observatory data repository (2024), World Health Organization. Data on population ageing and adults (≥20 years) with cardiovascular disease are from the Global Burden of Disease Study 2021 Results, Global Burden of Disease Collaborative Network.

Figure 2

Common features of adverse cardiac remodelling in obesity and ageing at different levels of integration. Both obesity and ageing affect cardiac structure and function, regardless of the associated risk factors. Neurohormonal stress and abnormal haemodynamics are key contributors to left ventricular diastolic dysfunction and left atrial remodelling in obese and/or aged hearts. At the tissue level, these alterations coincide with increased myocardial hypertrophy, fibrosis, and stiffness. At the cellular level, cardiac cells in obese hearts display several hallmarks of ageing, including impaired autophagy and proteostasis, altered mitochondrial function, increased oxidative stress, DNA instability, and premature accumulation of senescent cells.

Figure 3

Common features of adverse vascular remodelling in obesity and ageing at different levels of integration. The vascular system of individuals with obesity exhibits structural and functional alterations reminiscent of those observed in aged individuals. Despite distinct underlying mechanisms, both obesity and ageing cause arterial lumen enlargement, impaired vasodilatory function, increased peripheral vascular resistance, and chronic activation of the RAAS system, increasing the risk of hypertension. At the tissue level, obesity accelerates atherosclerotic remodelling, intima–media thickening, and vascular stiffening and dysfunction. At the cellular level, insulin resistance, mitochondrial dysfunction, and ROS accumulation drive these pathological alterations. RAAS, renin–angiotensin–aldosterone system; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor.

Figure 4

Meta-hallmarks of ageing and obesity in the cardiovascular system. This figure illustrates the shared molecular and cellular mechanisms between ageing and obesity that contribute to cardiac and vascular dysfunction, predisposing individuals to cardiovascular disease development and progression. These mechanisms include autophagy repression and loss of proteostasis (A), mitochondrial dysfunction and redox imbalance (B), DNA instability (C), cell senescence (D), altered neuro-hormonal signalling (E), and chronic inflammation (F). Features that are not shared are highlighted in red (if specific to obesity) or in blue (if specific to ageing) font. AngII, angiotensin-II; CRP, C-reactive protein; ER, endoplasmic reticulum; FA, fatty acids; IGF1, insulin-like growth factor 1; IL, interleukin; RAAS, renin–angiotensin–aldosterone system; ROS, reactive oxygen species; SASP, senescence-associated secretory phenotype; TNF, tumour necrosis factor; UPS, ubiquitin–proteasome system.

Figure 5

Common comorbidities in obesity and ageing. Obesity and ageing are associated with various pathological conditions that negatively impact cardiovascular and general health. These include, but are not limited to, hypertension, T2DM, vascular dementia, chronic kidney disease, sarcopenia, and osteoporosis. All of these conditions increase the risk of cardiovascular events and premature mortality, supporting the notion that obesity is an accelerator of cardiovascular ageing. CV, cardiovascular; T2DM, type 2 diabetes mellitus